Protective properties afforded by pioglitazone against intrastriatal LPS in Sprague–Dawley rats

Hunter, Randy L.; Choi, Dong‐Young; Ross, Stuart A.; Bing, Guoying

doi:10.1016/j.neulet.2007.12.019

Cited by 69 publications

(45 citation statements)

References 30 publications

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“…Similarly, in animal models of ischemia, stroke, hypertension, stress, and Parkinson's disease, which are also characterized as pro-inflammatory conditions, PPAR-γ agonists provide significant neuroprotection [100], [101], [102], [103], [104], [105], [106], [107], [108], [109], [110], [111], [112]. In AD animal models also, PPAR-γ agonists appear to reduce baseline inflammatory levels [24], [26], [113], [114].…”

Section: Discussionmentioning

confidence: 99%

Effects of Long-Term Pioglitazone Treatment on Peripheral and Central Markers of Aging

et al. 2010

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BackgroundThiazolidinediones (TZDs) activate peroxisome proliferator-activated receptor gamma (PPARγ) and are used clinically to help restore peripheral insulin sensitivity in Type 2 diabetes (T2DM). Interestingly, long-term treatment of mouse models of Alzheimer's disease (AD) with TZDs also has been shown to reduce several well-established brain biomarkers of AD including inflammation, oxidative stress and Aβ accumulation. While TZD's actions in AD models help to elucidate the mechanisms underlying their potentially beneficial effects in AD patients, little is known about the functional consequences of TZDs in animal models of normal aging. Because aging is a common risk factor for both AD and T2DM, we investigated whether the TZD, pioglitazone could alter brain aging under non-pathological conditions.Methods and FindingsWe used the F344 rat model of aging, and monitored behavioral, electrophysiological, and molecular variables to assess the effects of pioglitazone (PIO-Actos® a TZD) on several peripheral (blood and liver) and central (hippocampal) biomarkers of aging. Starting at 3 months or 17 months of age, male rats were treated for 4–5 months with either a control or a PIO-containing diet (final dose approximately 2.3 mg/kg body weight/day). A significant reduction in the Ca2+-dependent afterhyperpolarization was seen in the aged animals, with no significant change in long-term potentiation maintenance or learning and memory performance. Blood insulin levels were unchanged with age, but significantly reduced by PIO. Finally, a combination of microarray analyses on hippocampal tissue and serum-based multiplex cytokine assays revealed that age-dependent inflammatory increases were not reversed by PIO.ConclusionsWhile current research efforts continue to identify the underlying processes responsible for the progressive decline in cognitive function seen during normal aging, available medical treatments are still very limited. Because TZDs have been shown to have benefits in age-related conditions such as T2DM and AD, our study was aimed at elucidating PIO's potentially beneficial actions in normal aging. Using a clinically-relevant dose and delivery method, long-term PIO treatment was able to blunt several indices of aging but apparently affected neither age-related cognitive decline nor peripheral/central age-related increases in inflammatory signaling.

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Section: Discussionmentioning

confidence: 99%

Effects of Long-Term Pioglitazone Treatment on Peripheral and Central Markers of Aging

et al. 2010

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“…This hypothesis is suggested by the findings that: 1) in models of CNS injury, pioglitazone reduced mitochondrial dysfunction [36;37;75;93] and promoted glucose metabolism in astrocytes [19;66]; 2) pioglitazone reduced Aβ-induced astrocyte activation in the hippocampus [34]; 3) PPARγ is expressed in cortical astrocytes [17;58]; 4) astrocytes in the anterior cingulate cortex facilitate pain sensitization and inhibition [11;27;38;92]. This provides for the possibility that systemic pioglitazone administration produces anti-hyperalgesia through cortical, in addition to spinal, astrocytic mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Pioglitazone rapidly reduces neuropathic pain through astrocyte and nongenomic PPARγ mechanisms

Griggs

Donahue

Morgenweck

et al. 2015

Pain

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Repeated administration of peroxisome proliferator-activated receptor gamma (PPARγ) agonists reduces neuropathic pain-like behavior and associated changes in glial activation in the spinal cord dorsal horn. As PPARγ is a nuclear receptor, sustained changes in gene expression are widely believed to be the mechanism of pain reduction. However, we recently reported that a single intrathecal injection of pioglitazone, a PPARγ agonist, reduced hyperalgesia within 30 minutes, a time frame that is typically less than that required for genomic mechanisms. To determine the very rapid anti-hyperalgesic actions of PPARγ activation we administered pioglitazone to rats with spared nerve injury (SNI) and evaluated hyperalgesia. Pioglitazone inhibited hyperalgesia within 5 min of injection, consistent with a non-genomic mechanism. Systemic or intrathecal administration of GW9662, a PPARγ antagonist, inhibited the anti-hyperalgesic actions of intraperitoneal or intrathecal pioglitazone, suggesting a spinal PPARγ-dependent mechanism. To further address the contribution of non-genomic mechanisms, we blocked new protein synthesis in the spinal cord with anisomycin. When co-administered intrathecally, anisomycin did not change pioglitazone anti-hyperalgesia at an early 7.5 min timepoint, further supporting a rapid non-genomic mechanism. At later timepoints anisomycin reduced pioglitazone anti-hyperalgesia, suggesting a delayed recruitment of genomic mechanisms. Pioglitazone reduction of SNI-induced increases in GFAP expression occurred more rapidly than expected, within 60 min. We are the first to show that activation of spinal PPARγ rapidly reduces neuropathic pain independent from canonical genomic activity. We conclude that acute pioglitazone inhibits neuropathic pain in part by reducing astrocyte activation, and via both genomic and non-genomic PPARγ mechanisms.

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“…It has also been postulated that activation of PPAR receptors accentuates mitochondrial biogenesis through stimulation of peroxisome proliferator-activated receptor gamma coactivator-1 family of proteins, which positively regulate mitochondrial functions and metabolism (Mootha et al 2003;Houten and Auwerx 2004). In a recent study, it has been suggested that Pioglitazone decreases the expression of mitochondrial protein mitoNEET, which therefore protects against mitochondrial impairment observed in AD (Feinstein et al 2005;Hunter et al 2008).…”

Section: Mitochondria Biogenesis and Energy Utilizationmentioning

confidence: 99%

Neuroprotective mechanisms of peroxisome proliferator-activated receptor agonists in Alzheimer’s disease

Sodhi

Singh

Jaggi

2011

Naunyn-Schmiedeberg's Arch Pharmacol

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Alzheimer's disease (AD) is the most common causes of dementia accounting for 50-60% of all cases. The pathological hallmarks of AD are the formation of extracellular plaques consisting of amyloid-β protein, intracellular neurofibrillary tangles of hyperphosphorylated tau proteins and presence of chronic neuroinflammation causing progressive decline in memory and cognitive functions. The current therapeutic strategies to improve memory deficits aim at preventing the formation and accumulation of amyloid-β and tau phosphorylation. Beyond the plaque and tangle-related targets, other aspects of pathophysiology including molecular transport mechanism, oxidative damage, inflammation and glucose and lipid metabolism may also provide opportunities to slow down the progression of memory loss. A novel therapeutic approach to the treatment of AD is through the exploration of nuclear receptor agonists, peroxisome proliferator-activated receptors (PPARs), which have been clinically used as antidiabetic and dyslipidemic agents. The findings that PPAR agonists may possess antiamyloidogenic, anti-inflammatory, insulin-sensitizing, and cholesterol-lowering potential suggest that they could be interesting candidates for AD drugs. Through this review, we will discuss the probable pathophysiological mechanisms that may elicit the defending role of these receptors in brains of AD patients.

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Protective properties afforded by pioglitazone against intrastriatal LPS in Sprague–Dawley rats

Cited by 69 publications

References 30 publications

Effects of Long-Term Pioglitazone Treatment on Peripheral and Central Markers of Aging

Effects of Long-Term Pioglitazone Treatment on Peripheral and Central Markers of Aging

Pioglitazone rapidly reduces neuropathic pain through astrocyte and nongenomic PPARγ mechanisms

Neuroprotective mechanisms of peroxisome proliferator-activated receptor agonists in Alzheimer’s disease

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